Opioid medications have been increasingly used in the treatment of chronic pain in the U.S. A special panel for the American Geriatrics Society published guidelines in 2009 that recommended using opioids as a first line treatment of moderate to severe pain, pain-related impairment, and pain-related diminished quality of life for older adults. However, the safety of extended opioid therapy for chronic pain is unknown; most randomized controlled trials of opioid therapy for chronic pain have only monitored patients for less than six months of treatment. In contrast, some patients are treated with opioids for years. The most concerning safety risk due to opioid therapy, and the most directly attributable to opioid use, is prescription opioid overdose. Parallel to the increase in the medical use of opioids the rate of prescription opioid-related overdoses has increased sharply. Adults between the ages of 50 and 65 are at particularly elevated risk for unintentional and intentional overdose death, and individuals in this age range have elevated substance use and substance use-related adverse outcomes compared to adults age 65+ as well as prior generations during the same ages. Consequently, more data on the safety of opioid therapy in regards to overdose risk is crucial as this generation ages and develops chronic pain conditions requiring medical treatment in greater numbers. While opioid dose has been established as a predictor of opioid overdose death among patients treated for chronic pain in all-age samples, opioid regimen has not been examined in relation to prescription opioid overdose risk specifically for older adults. Additionally, there are limited data on how other patient and treatment characteristics relate to prescription opioid overdose risk. The proposed case-cohort study will be comprised of secondary analysis of Veterans Health Administration (VHA) records for 2000-2008, including pharmacy records, outpatient and inpatient treatment records, and cause-specific mortality data from the CDC's National Death Index, for VHA patients age 50 and older with chronic pain. The primary specific aims will be to (1) examine the association of opioid regimen (dose and schedule) with prescription opioid overdose among older adults receiving opioids; and (2) to determine how specific diagnoses (e.g., pain diagnoses, substance use disorders and other psychiatric conditions, dementia, COPD, CVD, and sleep apnea) and treatment utilization patterns relate to risk of prescription opioid overdose among older adults receiving opioids. Additional secondary analyses will examine these relationships in the subset of individuals between the ages of 50 and 65. Because of the potential for confounding by indication, analyses will include multivariable, marginal structural models, and instrumental variable approaches when needed. The findings of the proposed study are likely to have broad implications for improving the safety of the use of opioids in chronic pain treatment for current and future generations of older adults. PUBLIC HEALTH RELEVANCE: The long-term safety of opioid pain medications is unknown, despite the use of these medications to treat chronic pain becoming increasingly common. The most concerning safety risk for opioid medication use is overdose, and older adults are particularly at risk for both chronic pain and overdose. By examining how patient and treatment characteristics relate to risk of prescription opioid overdose mortality among older adults, this research will assist patients with chronic pain and their providers in making opioid treatment-related decisions.